Effects of a Novel Calcium Channel Agonist Dihydropyridine Analogue, Bay K 8644, on Pig Coronary Artery: Biphasic Mechanical Response and Paradoxical Potentiation of Contraction by Diltiazem and Nimodipine

Bay k 8644 is a structural analogue of the 1,4-dihydropyridines whose pharmacological actions on heart and vascular smooth muscle are opposite from those of nifedipine and other similar calcium antagonists. We have examined the action of Bay k 8644 ("calcium channel agonist") on isolated porcine coronary artery rings. The interactions between Bay k 8644 and the vasodilators isosorbide dinitrate (ISDN), diltiazem, and nimodipine were quantitated. Bay k 8644 produced a biphasic, dose-dependent mechanical response, with contraction occurring over the concentration range of 1-350 nM (ED50 = 11.4 nM) and relaxation observed at concentrations greater than 350 nM (IC50 = 5.7 microM). ISDN, diltiazem, and nimodipine relaxed, in a dose-dependent manner, maximal Bay k 8644-induced contractions. When the coronary rings were pretreated for 25-90 min with 80% inhibitory concentrations of these vasodilators, there was little or no effect by ISDN on Bay k 8644-induced contractions; however, there was a surprising potentiation by diltiazem and by nimodipine. Pretreatment of coronary rings with higher concentrations of ISDN or diltiazem caused an inhibition of Bay k 8644-induced contraction, while pretreatment with higher concentrations of nimodipine caused further potentiation of contraction elicited by Bay k 8644. Bay k 8644 increased the tension developed in response to high potassium (potential-operated channel activation) or histamine (receptor-operated channel activation). To account for the biphasic response to Bay k 8644 (dose-dependent contraction and relaxation), and the unexpected potentiation of Bay k 8644-induced contraction by nimodipine and by diltiazem, a molecular model is proposed for vascular smooth muscle in which Bay k 8644 functions as a partial calcium channel agonist at two functionally distinct 1,4-dihydropyridine "receptor sites."